In most T cell therapies, such as therapies using chimeric antigen receptor-expressing T cells (CAR), donor lymphocyte infusions (DLIs), or T cell add-back following hematopoietic stem cell transplants (HSCTs), the clinical relevance of demonstrated efficacy against tumors is somewhat diminished by the risk of off-target or off-organ adverse effects. Moreover, overzealous on-target effects, such as those directed against large tumor masses, can lead to cytokine storms, associated with tumor lysis syndrome (TLS), cytokine release syndrome (CRS) or macrophage activation syndrome (MAS). As a result, there is great interest in the development of a stable, reliable “suicide gene” that can eliminate transferred T cells or stem cells in the event that they trigger serious adverse events (SAEs), or become obsolete following treatment.
Methods for selectively killing therapeutic cells by inducing selective apoptosis, should an adverse event occur, are discussed in U.S. patent application Ser. No. 13/112,739, filed May 20, 2011, and entitled METHODS FOR INDUCING SELECTIVE APOPTOSIS, naming Malcolm K. Brenner as inventor. Modified caspase-9 polypeptides are discussed in U.S. patent application Ser. No. 13/792,135, filed Mar. 10, 2013, and entitled MODIFIED CASPASE POLYPEPTIDES AND USES THEREOF, naming David Spencer, et al., as inventors. Each patent application is hereby incorporated by reference herein in its entirety.
There is a need for a method for balancing the ability to rapidly remove the possible negative effects of donor cells used in cellular therapy, while retaining part or all of the beneficial effects of the therapy.